More than one third of the drugs listed in the US Pharmacopoeia and up to 40% new chemical entities discovered by pharmaceutical industry are poorly soluble or lipophilic compounds. The solubility of active pharmaceutical ingredients (APIs) is one of the most challenging issues in the improvement of many existing pharmaceutical formulations or the development of new chemical entities for commercialization, because the maximum achievable intraluminal drug concentration will limit the drug adsorption and bioavailability. Furthermore, improvements in bioavailability of APIs can yield to reduction in toxic secondary effects due to the use of less active, improvements in patient comfort due to the possibility of administering drugs without decreases in gastrointestinal pH, and improvements in patient compliance through a reduction of the number of doses required to achieve an adequate therapeutic level of the API. Therefore, the configuration of supersaturating drug delivery systems is a promising concept to obtain adequate oral bioavailability and improve overall pharmacokinetic properties. Additionally reduction in compound dose through better pharmacokinetic properties directly yields a reduction in costs of treatment.
Much effort has been made to enhance the solubility of the poorly soluble drugs to increase the adsorption and bioavailability. One most common method is to reduce the drug particle size to increase surface area and curvature of particles which may improve the solubility and bioavailability of the drugs. The use of nanoparticles may further enhance the capacity to generate supersaturation [see: Matteucci M E, et al., Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm 4:782-793. (2007); Overhoff K A, et al. Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing. Pharm Res 25:167-175. (2008)]. However, the nanoparticles with high surface energy are easily aggregated, more costly than porous particles described in the present invention and may possess additional toxicological profiles.
The amorphous form of a drug has the highest apparent solubility, so amorphous-based dosage forms are a popular formulation strategy for poorly water-soluble drugs. Spray-drying of drug compounds has been somewhat successful in processing amorphous formulations of drug compounds. However, amorphous drugs are thermodynamically unstable and often lead to re-crystallization in the presence of small amounts of moisture. It is a major issue to avoid recrystallization during storage. Scientific and economic efforts have been made to avoid recrystallization of the drugs adding to the overall cost of treatments.
One or more polymers (e.g., polyvinylpyrrolidone (PVP), polyethyleneglycols (PEG), polymethacrylates, cellulose derivatives, inulin, etc.) and/or (polymeric) surfactants (e.g., Muted 1 SP1, Gelucire1, poloxamer 407, etc.) have been used to disperse amorphous drug particles [see: Serajuddin A T. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058-1066; Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50:47-60. (2000); Vasconcelos T, et al. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 12:1068-1075 (2007)]. However, the incorporation of surfactants in formulation of poorly water-soluble drugs may cause irritation and side effects after oral administration in some cases, and they are liable to additional stability issues.
Recently, ordered nano (meso-)porous materials (e.g. silica) have been studied as carrier for the delivery of poorly water-soluble drugs [see: Salonen J, et al. Mesoporous silicon microparticles for oral drug delivery: Loading and release of five model drugs. J Control Release 108:362-374 (2005); Kaukonen A M, et al. Enhanced in vitro permeation of furosemide loaded into thermally carbonized mesoporous silicon (TCPSi) microparticles. Eur Pharm Biopharm 66:348-356 (2007); Shen S. C. Mesoporous materials excipients for poorly aqueous soluble ingredients, International Publication Number WO 2010/050897 A1]. Ordered nanoporous materials exhibits a 2-dimensionally or 3-dimensional ordered array of cylindrical or cage type pores (in the range of 2-50 nm) separated by thin silica walls. Bioactive drugs can be molecularly dispersed in these pores up to a certain loading (ca. 10-50% by weight). The influx diffusion of water to the pore surfaces provides for a rapid release of poorly water-soluble drugs if the drug compound is loaded in an amorphous state. It has been shown that the release of the weak base itraconazole from mesoporous materials gave rise to supersaturation in simulated gastric fluid; a subsequent pH shift to simulated intestinal fluid caused only limited precipitation and supersaturated concentrations were maintained for at least 4 h [see: Mellaerts R, et al. Enhanced release of itraconazole from ordered mesoporous SBA-15 silica materials. Chem Commun 13:1375-1377 (2007); Mellaerts R, et al. Ordered mesoporous silica induces pH-independent supersaturation of the basic low solubility compound itraconazole resulting in enhanced transepithelial transport. Int J Pharm 357:169-179 (2008); Mellaerts R, et al. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica. Eur J Pharm Biopharm 69:223-230 (2008)].
Ordered nanoporous materials have been attracting much attention because of the regular and adjustable pore size, different pore structures, high surface area and pore volume, high concentrations of silanol groups which make the channels like wet environment. Much work has been made to enhance the solubility of poorly water-soluble drugs on SBA-15 with the bigger pore size. Herein the present invention discloses methods that provide for enhancements in poorly water-soluble drugs loaded in the mesoporous material with the smaller pore size showing higher apparent solubility, where additionally 2d-hexagonal pore structure show improvements over 3d-cubic pore structures. In addition, the super-saturating state produced from the nanoporous materials with smaller pore size could maintain longer time than the samples with bigger pore size. Therefore, it is necessary to apply the mesoporous materials with the smaller pore size and 2-D pore structure to deliver poorly water-soluble drugs.
Recently, one mesoporous materials named nanoporous folic acid-templated materials (NFM-1) have been developed by using the folic acid as template [see: Garcia-Bennett A. E. Method for manufacturing mesoporous, materials so produced and use of mesoporous materials; International Publication Number WO 2009/101110 A2]. These materials have the 2-D hexagonal pore structure with the pore size of a range between 1.8 and 3.5 nm and varied morphologies. Especially important, we show that through the present invention they show faster dissolution rates and higher apparent solubility than the samples with the 3d-cubic pore structure and/or bigger pore size. The present invention is corroborated by in vivo data in an example of the use of the drug delivery vehicles disclosed here, showing enhancements of solubility in an actual pharmaceutical context, that is: enhancements of solubility of anti-retroviral ATV co-administered with proton pump inhibitors.
The present invention also relates to cosmetic active ingredients such as poorly soluble vitamins. Vitamins are essential nutrients that the human body needs in small amounts for various roles. Vitamins are divided into two groups: water-soluble (B-complex and C) and fat-soluble (A, D, E and K). Unlike water-soluble vitamins that need regular replacement in the body, fat-soluble vitamins are stored in the liver and fatty tissues, and are eliminated much more slowly than water-soluble vitamins.
Vitamin A, also called retinol, has many functions in the body. In addition to helping the eyes adjust to light changes, vitamin A plays an important role in bone growth, tooth development, reproduction, cell division and gene expression. Also, the skin, eyes and mucous membranes of the mouth, nose, throat and lungs depend on vitamin A to remain moist.
Retinol, along with other retinoids, has enjoyed increasing popularity as an active ingredient in skin care compositions, especially for acne, photoaging, and sun damage. However, more so than other retinoids, retinol tends to decompose on exposure to light, heat and oxygen. The problem of decomposition has been addressed to some extent by formulating retinol with antioxidants and chelating agents, and storing it in opaque or colored containers, and several patents and published applications describe water-in-oil emulsions containing retinol.
Softgel formulations have recently become of greater interest in the formulation of products for topical applications to the skin, because the softgel provide an attractive single us method for dispensing the product. However, it is well known that unmodified softgels are incompatible with water, and that typical emulsions, whether water-in-oil, will degrade the gelatin shell of a softgel. U.S. Pat. No. 5,587,149 discloses a softgel formulation for water soluble active ingredients, such as ascorbic acid (Vitamin C), where the fill material comprises an emulsion of which a first phase includes polyethylene glycol (into which the water-soluble active ingredients is dissolved and the second phase includes a silicone fluid). U.S. Pat. No. 4,826,828 reports a water-oil type emulsion wherein retinol, retinyl acetate and retynil palmitate are stabilized by an antioxidant such as BHT (butylated hydroxytoluene), or BHA (butylated hydroxytoluene). U.S. Pat. No. 4,720,353 reports a water-in-oil type emulsion wherein retinol is also stabilized with BHA, ascorbic acid or tocopherol.
EP 0440398 reports an oil-in-water type emulsion wherein retinol is stabilized with one or more kinds of water soluble antioxidants or chelating agents to improve chemical stability of retinol.
In the previous examples, the inventors refer to stabilizing retinol or retinoids, wherein antioxidants and chelating agents are the active elements. However the only difference between formulations or patented methodologies is the kind of chelating agents and properties of antioxidants used, so with these methods, the solubility of retinol remains poor as well as retinol keeps unprotected from factors such as oxygen, moisture or light. The present invention results in enhancements of solubility and stability of poorly soluble cosmetic actives, exemplified by Retinol.